Modified structure of the human serotonin transporter promoter.

Recently, several studies have reported an association between anxiety traits, affective disorders and autism and alleles of a functional promoter polymorphism (5HTT-LPR) in the human serotonin transporter (5HTT, SERT).1-3 The mechanistic basis for allelic differences in transporter transcription are presently unknown. To explore this issue, we cloned the human 5HTT promoter region from a PAC genomic library and now describe an unreported 381-bp insert between the polymorphic region and the transcription start site. We verified the presence of this novel sequence by Southern hybridization of genomic digests and PCR amplifications from multiple unrelated individuals. Sequence analysis of the novel region reveals a number of canonical transcription factor binding sites (eg AP1, Elk1, NFkappaB) that may be important in controlling the response of the 5HTT gene to regulatory factors. PCR studies of genomic templates reveal a low level of amplification of a deleted template matching the size of the originally reported 5HTT promoter. This deleted template is absent from PAC amplifications, suggesting that the human 5HTT promoter may exhibit in vivo instability. Molecular Psychiatry (2000) 5, 110-115.

Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency.

BACKGROUND: Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, and syncope and associated with postural tachycardia and plasma norepinephrine concentrations that are disproportionately high in relation to sympathetic outflow. We tested the hypothesis that impaired functioning of the norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance. METHODS: In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic norepinephrine spillover and clearance, and we sequenced the norepinephrine-transporter gene and evaluated its function. RESULTS: The patient had a high mean plasma norepinephrine concentration while standing, as compared with the mean (+/-SD) concentration in normal subjects (923 vs. 439+/-129 pg per milliliter [5.46 vs. 2.59+/-0.76 nmol per liter]), reduced systemic norepinephrine clearance (1.56 vs. 2.42+/-0.71 liters per minute), impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56+/-63 pg per milliliter [0.07 vs. 0.33+/-0.37 pmol per liter]), and a disproportionate increase in the concentration of plasma norepinephrine relative to that of dihydroxyphenylglycol. Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237) that resulted in more than a 98 percent loss of function as compared with that of the wild-type gene. Impairment of synaptic norepinephrine clearance may result in a syndrome characterized by excessive sympathetic activation in response to physiologic stimuli. The mutant allele in the proband's family segregated with the postural heart rate and abnormal plasma catecholamine homeostasis. CONCLUSIONS: Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance.